Metal-induced isomerization yields an intracellular chelator that disrupts bacterial iron homeostasis

The dwindling supply of Antibiotics that remain effective against drug-resistant Bacterial pathogens has precipitated efforts to identify new compounds that inhibit Bacterial growth using untapped mechanisms of action. Here, we report both (1) a high-throughput screening methodology designed to discover chemical perturbants of the essential, yet unexploited, process of Bacterial iron homeostasis, and (2) our findings from a small-molecule screen of more than 30,000 diverse small molecules that led to the identification and characterization of two spiro-indoline-thiadiazoles that disrupt iron homeostasis in bacteria. We show that these compounds are intracellular chelators with the capacity to exist in two isomeric states. Notably, these spiroheterocyles undergo a transition to an open merocyanine chelating form with Antibacterial activity that is specifically induced in the presence of its transition-metal target.